SUMMARY Cereblon (CRBN), a substrate receptor for the cullin–RING ubiquitin ligase 4 (CRL4) complex, is a direct protein target for thalidomide teratogenicity and antitumor activity of immunomodulatory drugs (IMiDs). Here we report that glutamine synthetase (GS) is an endogenous substrate of CRL4CRBN. Upon exposing cells to high glutamine concentration, GS is acetylated at lysines 11 and 14, yielding a degron that is necessary and sufficient for binding and ubiquitylation by CRL4CRBN and degradation by the proteasome. Binding of acetylated degron peptides to CRBN depends on an intact thalidomide-binding pocket but is not competitive with IMiDs. These findings reveal a feedback loop involving CRL4CRBN that adjusts GS protein levels in response to glutamine and uncover a new function for lysine acetylation.

Nonalcoholic fatty liver disease (NAFLD) is increasing in worldwide prevalence, closely tracking the obesity epidemic, but specific pharmaceutical treatments for NAFLD are lacking. Defining the key molecular pathways underlying the pathogenesis of NAFLD is essential for developing new drugs. Here we demonstrate that inhibition of gut-derived serotonin synthesis ameliorates hepatic steatosis through a reduction in liver serotonin receptor 2A (HTR2A) signaling. Local serotonin concentrations in the portal blood, which can directly travel to and affect the liver, are selectively increased by high-fat diet (HFD) feeding in mice. Both gut-specific Tph1 knockout mice and liver-specific Htr2a knockout mice are resistant to HFD-induced hepatic steatosis, without affecting systemic energy homeostasis. Moreover, selective HTR2A antagonist treatment prevents HFD-induced hepatic steatosis. Thus, the gut TPH1-liver HTR2A axis shows promise as a drug target to ameliorate NAFLD with minimal systemic metabolic effects.

Background: Interscalene brachial plexus block of the C5-C6 roots provides highly effective postoperative analgesia after shoulder surgery but usually results in hemidiaphragmatic paresis. Injection around the superior trunk of the brachial plexus is an alternative technique that may reduce this risk. The authors hypothesized that the superior trunk block would provide noninferior postoperative analgesia compared with the interscalene block and reduce hemidiaphragmatic paresis. Methods: Eighty patients undergoing arthroscopic shoulder surgery were randomized to receive a preoperative injection of 15 ml of 0.5% ropivacaine and 5 μg • ml −1 epinephrine around either (1) the C5-C6 nerve roots (interscalene block group) or (2) the superior trunk (superior trunk block group). The primary outcome was pain intensity 24 h after surgery measured on an 11-point numerical rating score; the prespecified noninferiority limit was 1. Diaphragmatic function was assessed using both ultrasonographic measurement of excursion and incentive spirometry by a blinded investigator before and 30 min after block completion. Results: Seventy-eight patients completed the study. The pain score 24 h postoperatively (means ± SDs) was 1.4 ± 1.0 versus 1.2 ± 1.0 in the superior trunk block (n = 38) and interscalene block (n = 40) groups, respectively. The mean difference in pain scores was 0.1 (95% CI, −0.3 to 0.6), and the upper limit of the 95% CI was lower than the prespecified noninferiority limit. Analgesic requirements and all other pain measurements were similar between groups. Hemidiaphragmatic paresis was observed in 97.5% of the interscalene block group versus 76.3% of the superior trunk block group (P = 0.006); paresis was complete in 72.5% versus 5.3% of the patients, respectively. The decrease in spirometry values from baseline was significantly greater in the interscalene block group. conclusions: The superior trunk block provided noninferior analgesia compared with interscalene brachial plexus block for up to 24 h after arthroscopic shoulder surgery and resulted in significantly less hemidiaphragmatic paresis.

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Pure laparoscopic donor right hepatectomy (PLDRH) is not a standard procedure for living donor liver transplantation but is safe and reproducible in the hands of experienced surgeons. However, the perioperative outcomes of PLDRH have not been fully evaluated yet. We used propensity score matching to compare the perioperative complications and postoperative short-term outcomes of donors undergoing PLDRH and open donor right hepatectomy (ODRH). A total of 325 consecutive donors who underwent elective, adult-to-adult right hepatectomy were initially screened. After propensity score matching, all patients were divided into two groups: PLDRH (n = 123) and ODRH (n = 123) groups. Perioperative complications and postoperative outcomes were compared between the two groups. Postoperative pulmonary complications were significantly more common in the ODRH than in the PLDRH group (54.5 vs. 31.7%, P < 0.001). The biliary complications (leak and stricture) were higher in PLDRH group than in the ODRH group (8% vs. 3%), but it failed to reach statistical significance (P = 0.167). Overall, surgical complication rates were similar between the two groups (P = 0.730). The opioid requirement during the first 7 postoperative days was higher in the ODRH group (686 vs. 568 mg, P < 0.001). The hospital stay and time to the first meal were shorter in the PLDRH than in the ODRH group (P = 0.003 and P < 0.001, respectively). PLDRH reduced the incidence of postoperative pulmonary complications and afforded better short-term postoperative outcomes compared to ODRH. However, surgical complication rates were similar in both groups.Laparoscopic liver surgery has become widely accepted, affording many benefits including fewer overall complications, less blood loss, lower pain scores, better donor quality-of-life during the early postoperative period, and a shorter hospital stay, compared to open surgery 1-3 . As surgical techniques advanced over time, laparoscopic surgery for living donor liver transplantation (LDLT) became possible 2 . After the first successful reports of laparoscopic left lateral sectionectomy during adult-to-child LDLT in 2002 4 , many centers adopted the laparoscopic approach as the standard for living liver donors undergoing small graft resections 5,6 . However, the use of laparoscopic procedures to perform larger graft resections (such as right hepatectomies) was initially limited by technical complexities and the steep learning curve associated with the procedures. However, a series of laparoscopic right hepatectomies performed by experienced surgeons at living donor centers showed that the results open Scientific RepoRtS | (2020) 10:5314 | https://doi.

This study was registered at the Clinical Trial Registry of Korea, identifier KCT0002119.

BACKGROUND Erector spinae plane block (ESPB) has been reported to manage postoperative pain effectively after various types of surgery. However, there has been a lack of study on the effect of ESPB after liver resection. OBJECTIVES To investigate the analgesic effects of ESPB on pain control after laparoscopic liver resection compared with conventional pain management. DESIGN Prospective, randomised controlled study. SETTING A single tertiary care centre from February 2019 to February 2020. PATIENTS A total of 70 patients scheduled to undergo laparoscopic liver resection. INTERVENTIONS In the control group (n = 35), no procedure was performed. In the ESPB group (n = 35), ESPB was performed after induction of general anaesthesia. A total of 40 ml of ropivacaine 0.5% was injected at the T9 level bilaterally. After surgery, intravenous fentanyl patient-controlled analgesia was initiated. Fentanyl and hydromorphone were administered as rescue analgesics. MAIN OUTCOME MEASURES The primary outcome was the cumulative postoperative opioid consumption at 24 h (morphine equivalent). The secondary outcomes were rescue opioid (fentanyl) dose in the postanaesthesia care unit (PACU) and pain severity at 1, 6, 12, 24, 48 and 72 h, assessed using a numerical rating scale (NRS) score. RESULTS The median [IQR] postoperative opioid consumption during 24 hours following surgery was 48.2 [17.1] mg in the control group and 45.5 [35.8] mg in the ESPB group (median difference, 4.2 mg; 95% CI, −4.2 to 13.3 mg; P = 0.259). Conversely, rescue opioid in PACU was 5.3 [5.0] mg in the control group and 3.0 [1.5] mg in the ESPB group (median difference, 2.5 mg; 95% CI, 1.0 to 5.0 mg; P < 0.001). There was no significant difference in NRS scores point between the groups at any time. CONCLUSION ESPB does not provide analgesic effect within 24 h after laparoscopic liver resection. TRIAL REGISTRATION Clinical Trial Registry of Korea (https://cris.nih.go.kr.), identifier: KCT0003549)

BackgroundIncreased intra-abdominal pressure during laparoscopic surgery causes cephalad displacement of the diaphragm, resulting in the formation of atelectasis, which can be overcome by positive end-expiratory pressure (PEEP). The aim of this prospective study was to investigate the level of optimal PEEP to maintain adequate arterial oxygenation and hemodynamics during robot-assisted laparoscopic radical prostatectomy (RLRP).MethodsOne hundred patients undergoing RLRP were randomly allocated to one of five groups (n = 20) (0, 3, 5, 7 and 10 cmH2O of PEEP). Hemodynamic variables and respiratory parameters were measured at baseline with the patient in the supine position; at 30 min, 1, 2, 3 and 4 h during CO2 insufflation with the patient in the post-Trendelenburg position; and after deflation in the supine position with increasing PEEP.ResultsThe PaO2 levels and alveolar-arterial difference in oxygen tension (AaDO2) were improved in patients with PEEPs compared with patients in whom PEEP was not used. The application of PEEP (10 cmH2O) resulted in higher PaO2 levels compared to those with lower PEEP levels, but excessive peak airway pressure (PAP) was sometimes observed. The application of a PEEP of 7 cmH2O resulted in similar PaO2 levels without causing excessive PAP. There was a significant difference in central venous pressure between the groups, but there were no significant differences in heart rate, mean arterial pressure or minute ventilation between the groups.ConclusionsA PEEP of 7 cmH2O is associated with the greater improvement of PaO2 and AaDO2 without causing excessive PAP during RLRP.